Mechanisms of Perineural Invasion

 

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Abstract

Perineural invasion (PNI) is the neoplastic invasion of nerves. PNI is widely recognized as an important adverse pathological feature of many malignancies, including pancreatic, prostate, and head and neck cancers and is associated with a poor prognosis. Despite widespread acknowledgment of the clinical significance of PNI, the mechanisms underlying its pathogenesis remain largely unknown. Recent theories of PNI pathogenesis have placed a significant emphasis on the active role of the nerve microenvironment, with PNI resulting from well-orchestrated reciprocal interactions between cancer and host. Elucidating the mechanisms involved in PNI may translate into targeted therapies for this ominous process.

• References

• 1 Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol 1985; 94 (4 Pt 1) 426-427
  PubMedGoogle Scholar
• 2 Soo KC, Carter RL, O'Brien CJ, Barr L, Bliss JM, Shaw HJ. Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope 1986; 96 (10) 1145-1148
  PubMedGoogle Scholar
• 3 Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1998; 124 (6) 637-640
  CrossrefPubMedGoogle Scholar
• 4 Takahashi T, Ishikura H, Motohara T, Okushiba S, Dohke M, Katoh H. Perineural invasion by ductal adenocarcinoma of the pancreas. J Surg Oncol 1997; 65 (3) 164-170
  CrossrefPubMedGoogle Scholar
• 5 Cruveilheir J. Maladies Des Nerfs Anatomie Pathlogique Du Corps Humain. Paris, France: JB Bailliere; 1835
  Google Scholar
• 6 Larson DL, Rodin AE, Roberts DK, O'Steen WK, Rapperport AS, Lewis SR. Perineural lymphatics: myth or fact. Am J Surg 1966; 112 (4) 488-492
  CrossrefPubMedGoogle Scholar
• 7 Akert K, Sandri C, Weibel ER, Peper K, Moor H. The fine structure of the perineural endothelium. Cell Tissue Res 1976; 165 (3) 281-295
  PubMedGoogle Scholar
• 8 Stolinski C. Structure and composition of the outer connective tissue sheaths of peripheral nerve. J Anat 1995; 186 (Pt 1) 123-130
  Google Scholar
• 9 Olsson Y. Microenvironment of the peripheral nervous system under normal and pathological conditions. Crit Rev Neurobiol 1990; 5 (3) 265-311
  PubMedGoogle Scholar
• 10 Amit M, Binenbaum Y, Trejo-Leider L , et al. International collaborative validation of intraneural invasion as a prognostic marker in adenoid cystic carcinoma of the head and neck. Head Neck 2015; 37 (7) 1038-1045
  CrossrefPubMedGoogle Scholar
• 11 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4 (1) 71-78
  CrossrefPubMedGoogle Scholar
• 12 Kieseier BC, Hartung HP, Wiendl H. Immune circuitry in the peripheral nervous system. Curr Opin Neurol 2006; 19 (5) 437-445
  CrossrefPubMedGoogle Scholar
• 13 Cavel O, Shomron O, Shabtay A , et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res 2012; 72 (22) 5733-5743
  CrossrefPubMedGoogle Scholar
• 14 Zeng L, Guo Y, Liang J , et al. Perineural Invasion and TAMs in Pancreatic Ductal Adenocarcinomas: Review of the Original Pathology Reports Using Immunohistochemical Enhancement and Relationships with Clinicopathological Features. J Cancer 2014; 5 (9) 754-760
  CrossrefPubMedGoogle Scholar
• 15 Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432 (7015) 332-337
  CrossrefPubMedGoogle Scholar
• 16 Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006; 6 (5) 392-401
  CrossrefPubMedGoogle Scholar
• 17 Bunge MB, Wood PM, Tynan LB, Bates ML, Sanes JR. Perineurium originates from fibroblasts: demonstration in vitro with a retroviral marker. Science 1989; 243 (4888) 229-231
  CrossrefPubMedGoogle Scholar
• 18 Jessen KR. Glial cells. Int J Biochem Cell Biol 2004; 36 (10) 1861-1867
  CrossrefPubMedGoogle Scholar
• 19 Scheib J, Höke A. Advances in peripheral nerve regeneration. Nat Rev Neurol 2013; 9 (12) 668-676
  Google Scholar
• 20 Demir IE, Boldis A, Pfitzinger PL , et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J Natl Cancer Inst 2014; 106 (8) pii: dju184
  PubMedGoogle Scholar
• 21 Deborde S, Omelchenko T, Lyubchik A , et al. Schwann cells induce cancer dispersion and invasion. J Clin Invest 2016; . In press.
  PubMedGoogle Scholar
• 22 Ayala GE, Wheeler TM, Shine HD , et al. In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 2001; 49 (3) 213-223
  CrossrefPubMedGoogle Scholar
• 23 Dai H, Li R, Wheeler T , et al. Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach. Hum Pathol 2007; 38 (2) 299-307
  CrossrefPubMedGoogle Scholar
• 24 Bakst RL, Lee N, He S , et al. Radiation impairs perineural invasion by modulating the nerve microenvironment. PLoS ONE 2012; 7 (6) e39925
  CrossrefPubMedGoogle Scholar
• 25 He S, He S, Chen CH , et al. The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol Cancer Res 2015; 13 (2) 380-390
  CrossrefPubMedGoogle Scholar
• 26 Gil Z, Cavel O, Kelly K , et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 2010; 102 (2) 107-118
  CrossrefPubMedGoogle Scholar
• 27 Abiatari I, DeOliveira T, Kerkadze V , et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. Mol Cancer Ther 2009; 8 (6) 1494-1504
  CrossrefPubMedGoogle Scholar
• 28 Braun BS, Tuveson DA, Kong N , et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci U S A 2004; 101 (2) 597-602
  CrossrefPubMedGoogle Scholar
• 29 Stopczynski RE, Normolle DP, Hartman DJ , et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 2014; 74 (6) 1718-1727
  CrossrefPubMedGoogle Scholar
• 30 Magnon C, Hall SJ, Lin J , et al. Autonomic nerve development contributes to prostate cancer progression. Science 2013; 341 (6142) 1236361
  CrossrefPubMedGoogle Scholar
• 31 Meng E, Sun GH, Wu ST , et al. Value of prostate-specific antigen in the staging of Taiwanese patients with newly diagnosed prostate cancer. Arch Androl 2003; 49 (6) 471-474
  PubMedGoogle Scholar
• 32 Pour PM, Egami H, Takiyama Y. Patterns of growth and metastases of induced pancreatic cancer in relation to the prognosis and its clinical implications. Gastroenterology 1991; 100 (2) 529-536
  CrossrefPubMedGoogle Scholar
• 33 Cabanillas R, Secades P, Rodrigo JP, Astudillo A, Suárez C, Chiara MD. Orthotopic murine model of head and neck squamous cell carcinoma [in Spanish]. Acta Otorrinolaringol Esp 2005; 56 (3) 89-95
  CrossrefPubMedGoogle Scholar
• 34 Chernichenko N, Linkov G, Li P , et al. Oncolytic vaccinia virus therapy of salivary gland carcinoma. JAMA Otolaryngol Head Neck Surg 2013; 139 (2) 173-182
  CrossrefPubMedGoogle Scholar
• 35 He S, Chen CH, Chernichenko N , et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A 2014; 111 (19) E2008-E2017
  CrossrefPubMedGoogle Scholar
• 36 Durbec P, Marcos-Gutierrez CV, Kilkenny C , et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature 1996; 381 (6585) 789-793
  CrossrefPubMedGoogle Scholar
• 37 Okada Y, Takeyama H, Sato M , et al. Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neurotrophic factor (GDNF). Int J Cancer 1999; 81 (1) 67-73
  CrossrefPubMedGoogle Scholar
• 38 Chuang JY, Tsai CF, Chang SW , et al. Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma. Oral Oncol 2013; 49 (12) 1103-1112
  CrossrefPubMedGoogle Scholar
• 39 Treanor JJ, Goodman L, de Sauvage F , et al. Characterization of a multicomponent receptor for GDNF. Nature 1996; 382 (6586) 80-83
  CrossrefPubMedGoogle Scholar
• 40 Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002; 3 (5) 383-394
  CrossrefPubMedGoogle Scholar
• 41 Trupp M, Scott R, Whittemore SR, Ibáñez CF. Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. J Biol Chem 1999; 274 (30) 20885-20894
  CrossrefPubMedGoogle Scholar
• 42 Ceyhan GO, Giese NA, Erkan M , et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg 2006; 244 (2) 274-281
  CrossrefPubMedGoogle Scholar
• 43 Ceyhan GO, Bergmann F, Kadihasanoglu M , et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007; 56 (4) 534-544
  CrossrefPubMedGoogle Scholar
• 44 Gao L, Bo H, Wang Y, Zhang J, Zhu M. Neurotrophic Factor Artemin Promotes Invasiveness and Neurotrophic Function of Pancreatic Adenocarcinoma In Vivo and In Vitro. Pancreas 2015; 44 (1) 134-143
  CrossrefPubMedGoogle Scholar
• 45 Ketterer K, Rao S, Friess H, Weiss J, Büchler MW, Korc M. Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 2003; 9 (14) 5127-5136
  PubMedGoogle Scholar
• 46 Jia S, Wang W, Hu Z , et al. BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma. Oral Oncol 2015; 51 (1) 64-70
  CrossrefPubMedGoogle Scholar
• 47 Kowalski PJ, Paulino AF. Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor. Hum Pathol 2002; 33 (9) 933-936
  CrossrefPubMedGoogle Scholar
• 48 Okugawa Y, Tanaka K, Inoue Y , et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer 2013; 108 (1) 121-130
  CrossrefPubMedGoogle Scholar
• 49 Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 1999; 81 (3) 417-427
  CrossrefPubMedGoogle Scholar
• 50 Amit M, Na'ara S, Sharma K , et al. Elective neck dissection in patients with head and neck adenoid cystic carcinoma: an international collaborative study. Ann Surg Oncol 2015; 22 (4) 1353-1359
  CrossrefPubMedGoogle Scholar
• 51 Sclabas GM, Fujioka S, Schmidt C , et al. Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 2005; 11 (2 Pt 1) 440-449
  PubMedGoogle Scholar
• 52 Miknyoczki SJ, Wan W, Chang H , et al. The neurotrophin-trk receptor axes are critical for the growth and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice. Clin Cancer Res 2002; 8 (6) 1924-1931
  PubMedGoogle Scholar
• 53 Zhu Z, Friess H, diMola FF , et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol 1999; 17 (8) 2419-2428
  CrossrefPubMedGoogle Scholar
• 54 Ma J, Jiang Y, Jiang Y, Sun Y, Zhao X. Expression of nerve growth factor and tyrosine kinase receptor A and correlation with perineural invasion in pancreatic cancer. J Gastroenterol Hepatol 2008; 23 (12) 1852-1859
  CrossrefPubMedGoogle Scholar
• 55 Okada Y, Eibl G, Guha S, Duffy JP, Reber HA, Hines OJ. Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin Exp Metastasis 2004; 21 (4) 285-292
  CrossrefPubMedGoogle Scholar
• 56 Kolokythas A, Cox DP, Dekker N, Schmidt BL. Nerve growth factor and tyrosine kinase A receptor in oral squamous cell carcinoma: is there an association with perineural invasion?. J Oral Maxillofac Surg 2010; 68 (6) 1290-1295
  CrossrefPubMedGoogle Scholar
• 57 Murphy PM. Chemokines and the molecular basis of cancer metastasis. N Engl J Med 2001; 345 (11) 833-835
  CrossrefPubMedGoogle Scholar
• 58 Mackay CR. Chemokines: immunology's high impact factors. Nat Immunol 2001; 2 (2) 95-101
  CrossrefPubMedGoogle Scholar
• 59 Van Steenwinckel J, Reaux-Le Goazigo A, Pommier B , et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci 2011; 31 (15) 5865-5875
  CrossrefPubMedGoogle Scholar
• 60 Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst 2010; 102 (8) 522-528
  CrossrefPubMedGoogle Scholar
• 61 Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004; 20 (5) 1150-1160
  CrossrefPubMedGoogle Scholar
• 62 Marchesi F, Piemonti L, Fedele G , et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res 2008; 68 (21) 9060-9069
  CrossrefPubMedGoogle Scholar
• 63 Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J Neuroimmunol 2010; 224 (1–2) 39-44
  CrossrefPubMedGoogle Scholar
• 64 Alier KA, Chen Y, Sollenberg UE, Langel U, Smith PA. Selective stimulation of GalR1 and GalR2 in rat substantia gelatinosa reveals a cellular basis for the anti- and pro-nociceptive actions of galanin. Pain 2008; 137 (1) 138-146
  CrossrefPubMedGoogle Scholar
• 65 Hobson SA, Bacon A, Elliot-Hunt CR , et al. Galanin acts as a trophic factor to the central and peripheral nervous systems. EXS 2010; 102: 25-38
  PubMedGoogle Scholar
• 66 Hulse RP, Wynick D, Donaldson LF. Activation of the galanin receptor 2 in the periphery reverses nerve injury-induced allodynia. Mol Pain 2011; 7: 26
  CrossrefPubMedGoogle Scholar
• 67 Rauch I, Kofler B. The galanin system in cancer. EXS 2010; 102: 223-241
  PubMedGoogle Scholar
• 68 Banerjee R, Henson BS, Russo N, Tsodikov A, D'Silva NJ. Rap1 mediates galanin receptor 2-induced proliferation and survival in squamous cell carcinoma. Cell Signal 2011; 23 (7) 1110-1118
  CrossrefPubMedGoogle Scholar
• 69 Scanlon CS, Banerjee R, Inglehart RC , et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat Commun 2015; 6: 6885
  CrossrefPubMedGoogle Scholar
• 70 Chen P, Cescon M, Bonaldo P. The Role of Collagens in Peripheral Nerve Myelination and Function. Mol Neurobiol 2015; 52 (1) 216-225
  CrossrefPubMedGoogle Scholar
• 71 Okada Y, Eibl G, Duffy JP, Reber HA, Hines OJ. Glial cell-derived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase-9 in human pancreatic cancer. Surgery 2003; 134 (2) 293-299
  CrossrefPubMedGoogle Scholar
• 72 Ellenrieder V, Alber B, Lacher U , et al. Role of MT-MMPs and MMP-2 in pancreatic cancer progression. Int J Cancer 2000; 85 (1) 14-20
  CrossrefPubMedGoogle Scholar
• 73 Durlik M, Gardian K. Metalloproteinase 2 and 9 activity in the development of pancreatic cancer. Pol Przegl Chir 2012; 84 (8) 377-382
  PubMedGoogle Scholar
• 74 Overall CM, Kleifeld O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006; 6 (3) 227-239
  CrossrefPubMedGoogle Scholar
• 75 Ayala GE, Dai H, Powell M , et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 2008; 14 (23) 7593-7603
  CrossrefPubMedGoogle Scholar
• 76 Olar A, He D, Florentin D, Ding Y, Wheeler T, Ayala G. Biological correlates of prostate cancer perineural invasion diameter. Hum Pathol 2014; 45 (7) 1365-1369
  CrossrefPubMedGoogle Scholar
• 77 Albo D, Akay CL, Marshall CL , et al. Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer 2011; 117 (21) 4834-4845
  CrossrefPubMedGoogle Scholar
• 78 de Wit J, Verhaagen J. Role of semaphorins in the adult nervous system. Prog Neurobiol 2003; 71 (2–3) 249-267
  CrossrefPubMedGoogle Scholar
• 79 Müller MW, Giese NA, Swiercz JM , et al. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int J Cancer 2007; 121 (11) 2421-2433
  CrossrefPubMedGoogle Scholar
• 80 Ding Y, He D, Florentin D , et al. Semaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer. Clin Cancer Res 2013; 19 (22) 6101-6111
  CrossrefPubMedGoogle Scholar
• 81 Li HS, Chen JH, Wu W , et al. Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell 1999; 96 (6) 807-818
  CrossrefPubMedGoogle Scholar
• 82 Göhrig A, Detjen KM, Hilfenhaus G , et al. Axon guidance factor SLIT2 inhibits neural invasion and metastasis in pancreatic cancer. Cancer Res 2014; 74 (5) 1529-1540
  CrossrefPubMedGoogle Scholar
• 83 Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 2010; 10 (3) 165-180
  CrossrefPubMedGoogle Scholar
• 84 Wykosky J, Debinski W. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol Cancer Res 2008; 6 (12) 1795-1806
  CrossrefPubMedGoogle Scholar
• 85 Shao Z, Zhu F, Song K, Zhang H, Liu K, Shang Z. EphA2/ephrinA1 mRNA expression and protein production in adenoid cystic carcinoma of salivary gland. J Oral Maxillofac Surg 2013; 71 (5) 869-878
  CrossrefPubMedGoogle Scholar
• 86 Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004; 4 (2) 118-132
  CrossrefPubMedGoogle Scholar
• 87 Bockman DE, Büchler M, Beger HG. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology 1994; 107 (1) 219-230
  CrossrefPubMedGoogle Scholar
• 88 Neuberger TJ, Cornbrooks CJ. Transient modulation of Schwann cell antigens after peripheral nerve transection and subsequent regeneration. J Neurocytol 1989; 18 (5) 695-710
  CrossrefPubMedGoogle Scholar
• 89 Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 2007; 10 (1) 19-26
  CrossrefPubMedGoogle Scholar
• 90 Kameda K, Shimada H, Ishikawa T , et al. Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion. Cancer Lett 1999; 137 (2) 201-207
  CrossrefPubMedGoogle Scholar
• 91 Shang J, Sheng L, Wang K, Shui Y, Wei Q. Expression of neural cell adhesion molecule in salivary adenoid cystic carcinoma and its correlation with perineural invasion. Oncol Rep 2007; 18 (6) 1413-1416
  PubMedGoogle Scholar
• 92 Li R, Wheeler T, Dai H, Ayala G. Neural cell adhesion molecule is upregulated in nerves with prostate cancer invasion. Hum Pathol 2003; 34 (5) 457-461
  CrossrefPubMedGoogle Scholar
• 93 Solares CA, Brown I, Boyle GM, Parsons PG, Panizza B. Neural cell adhesion molecule expression: no correlation with perineural invasion in cutaneous squamous cell carcinoma of the head and neck. Head Neck 2009; 31 (6) 802-806
  CrossrefPubMedGoogle Scholar
• 94 Chen-Tsai CP, Colome-Grimmer M, Wagner Jr RF. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol Surg 2004; 30 (7) 1009-1016
  PubMedGoogle Scholar
• 95 Vyas AA, Patel HV, Fromholt SE , et al. Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A 2002; 99 (12) 8412-8417
  CrossrefPubMedGoogle Scholar
• 96 Swanson BJ, McDermott KM, Singh PK, Eggers JP, Crocker PR, Hollingsworth MA. MUC1 is a counter-receptor for myelin-associated glycoprotein (Siglec-4a) and their interaction contributes to adhesion in pancreatic cancer perineural invasion. Cancer Res 2007; 67 (21) 10222-10229
  CrossrefPubMedGoogle Scholar
• 97 Lindner J, Rathjen FG, Schachner M. L1 mono- and polyclonal antibodies modify cell migration in early postnatal mouse cerebellum. Nature 1983; 305 (5933) 427-430
  CrossrefPubMedGoogle Scholar
• 98 Thies A, Schachner M, Moll I , et al. Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Eur J Cancer 2002; 38 (13) 1708-1716
  CrossrefPubMedGoogle Scholar
• 99 Boo YJ, Park JM, Kim J , et al. L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer. Ann Surg Oncol 2007; 14 (5) 1703-1711
  CrossrefPubMedGoogle Scholar
• 100 Ben QW, Wang JC, Liu J , et al. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann Surg Oncol 2010; 17 (8) 2213-2221
  CrossrefPubMedGoogle Scholar
• 101 Zhao CM, Hayakawa Y, Kodama Y , et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med 2014; 6 (250) 250ra115
  CrossrefPubMedGoogle Scholar